Abstract
Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs’s cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew’s Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.
Introduction
The phaeochromocytoma and paraganglioma (PPGL) tumour group is the most heritable of tumours, with at least 40% of cases arising from a pathogenic germline mutation (Dahia 2014). Of these, around half are caused by pathogenic variants (PVs) in genes encoding critical enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase(SDH). PVs in SDH subunits result in loss of function of the SDH protein complex; SDH-deficient tumours are in the cluster of PPGL with a pseudo-hypoxic cellular response and the greatest potential for metastatic disease (Nölting et al. 2022), and the metastatic tendency is particularly apparent with PVs in the SDHB subunit. Inheritance of SDH alleles is assumed to follow Mendelian laws of segregation, with a probability of 50% from each parent, but confirmation of this in clinical practice is made difficult by the highly variable penetrance across the subunits SDH-A to -D (Tufton et al. 2019) and the rarity of SDH-deficient tumours in general.
There exist monogenic familial diseases which are not necessarily transmitted according to Mendelian laws of inheritance, including Factor V Leiden deficiency (Infante-Rivard & Weinberg 2005), Long QT syndrome (Imboden et al. 2006), and some of the spinocerebellar ataxias (Riess et al. 1997, Bettencourt et al. 2008) (Table 1). The departure from a transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD) (Pardo-Manuel de Villena et al. 2000). There are five key timepoints at which TRD can occur (Huang et al. 2013): (i) germline selection (e.g. mutation, recombination, non-allelic gene conversion) during mitosis; (ii) mechanisms that occur in meiosis and prior to fertilization known as meiotic drive, where the structural characteristics of a certain chromatid result in increased transmission during oogenesis (maternal germline) or spermatogenesis (paternal germline); (iii) gametic competition (by sperm) prior to fertilization, resulting in gamete selection; (iv) imprint resetting at the post-implantation stage, when parental imprints are erased and re-established; and (v) post-fertilization mechanisms of embryonic or neonatal lethality from the inherited allele, resulting in differential survival of offspring. We suggest that at this time point, advantageous selection may also occur (Fig. 1).
Five key timepoints at which transmission ratio distortion may occur. Created with https://www.biorender.com/.
Citation: Endocrine-Related Cancer 30, 5; 10.1530/ERC-22-0233
Genes known to demonstrate transmission ratio distortion.
| Gene | Function |
|---|---|
| Relates to tumourigenesis | |
| CDKN1C | Tumour suppressor |
| HRAS1 | Oncogene |
| IGF2 | Intestinal adenoma |
| RB-1 | Retinoblastoma tumour suppressor |
| SIRT3 | Node-positive breast cancer |
| TNFa and TNFb | Tumour necrosis |
| Relates to neurological development | |
| ARX | Non-syndromic intellectual disability and brain malformations |
| CTDP1 | Congenital cataract, facial dysmorphism, peripheral neuropathy |
| DMPK | Muscular dystrophy |
| HASH2 (ASCL2) | Neuronal precursor for central and peripheral nervous systems |
| SCA1, SCA3 (ATXN3) | Spinocerebellar ataxia types 1 and 3 (respectively) |
| SMN1 | Spinal muscular atrophy |
| TH | Neuropathology |
| Overlap of roles in tumourigenesis and early neurological development | |
| DBC1, CDK5RAP2, MEGF9 | Neuronal differentiation; bladder cancer |
| MTHFR | Acute leukaemia; colon cancer; neural tube defects |
| NBPF8 and HFE2 | Neuroblastoma tumour suppressor, cognitive development; iron metabolism |
| Other | |
| ATG16L1, DLG5 | Inflammatory bowel disease |
| BHLHA9 | Split-hand/foot malformation +/− Long bone deficiency |
| CLC1, IGFR2 (FCGR2B) | Autoimmunity |
| F2 (Factor II / thrombin) | Thrombosis |
| F5 (Factor V Leiden) | Thrombophilia |
| HSP70.1 | Graft vs host disease |
| INS | Hyperinsulinism |
| KCNQ1, KCNH2 | Long QT syndrome |
| STX16-GNAS | Autosomal dominant pseudohypoparathyroidism type 1b |
| SUPT3H-MIRN586-RUNX2 | Cleft palate; skeletal morphogenesis; haematological neoplasia |
| TGFB1 | Cystic fibrosis severity and endophenotype |
Data from Huang et al. (2013). See references for further details.
Our interest in whether SDH PVs are inherited according to Mendelian laws of segregation or in an imbalanced, distorted way arose anecdotally: an SDHB PV carrier underwent pre-implantation genetic testing and reported that high numbers of embryos harboured the affected allele. We sought to assess whether TRD occurs in the transmission of SDHB PVs and posit that a post-fertilization survival advantage is the cause.
Materials and methods
This study has been conducted with 41 families of a discovery cohort in Australia, from Royal North Shore Hospital (RNSH), and a validation cohort in the United Kingdom, from St. Bartholomew’s Hospital (SBH), together representing a range of different PVs in the SDHB gene. Inclusion criteria were a confirmed SDHB PV and a pedigree available for at least two generations (such that data on transmission could be analysed from the second generation onwards). Probands were defined as the first individual in a family to be diagnosed with an SDHB PV after presenting with a PPGL. PVs were classified as loss of function (nonsense, splicing, deletion, or frameshift) or missense. PVs were defined as being in the proximal region of the SDHB gene if they occurred in exons 1–3 or intronic regions up to IVS3. Ethics approval was obtained from the Northern Sydney Local Health District Ethics Committee for the discovery cohort (Ref: 2022/ETH01880), including waiver of consent, and Cambridge East Medical Research Ethics Committee for the validation cohort (Ref: 06/Q0104/133). Patients provided consent after a full explanation of the purpose of the study.
Statistical analysis was performed using IBM SPSS version 28. The forest plot figure was produced using GraphPad Prism version 9. Categorical data were tested with the binomial test to obtain a true estimate, with 95% confidence intervals using the Clopper–Pearson method. Continuous data were assessed with the exact Mann–Whitney test for non-parametric data. A P-value ≤ 0.05 (two-tailed) was considered statistically significant. Results that were not significant were assessed for heterogeneity with Levene’s test. Several sensitivity analyses were undertaken in this study by (i) excluding probands, (ii) excluding families with incomplete family pedigree data, and (iii) excluding untested participants younger than 20 years of age. Potential predictors of TRD were assessed in the cohort that underwent genetic testing and the cohort with complete family data, using a generalized linear model with binary logistic regression to perform a multivariate analysis. Explanatory variables included in this model were sex, genotype, parent of origin, birth order, and family size.
Results
A total of 575 participants from 82 families from RNSH and SBH were assessed. There was a difference between centres in the proportion that underwent genetic testing and the number of generations assessed in each family (Table 2). Of the 575 participants assessed, 503 underwent genetic testing, with 316 found to harbour an SDHB PV. Thirty-six different SDHB PVs were represented in the combined cohort: 12 missense PVs were present in 29 families, and a further 24 PVs were loss of function mutations (Supplementary Table 1, see section on supplementary materials given at the end of this article). Disease had manifested in approximately 19% of SDHB participants at any timepoint, which is similar to reported disease penetrance in the literature (Benn et al. 2018, Rijken et al. 2018). In the validation cohort, most families (61%) were represented by three generations and most nuclear families had two or three offspring (biological children.)
Baseline characteristics of SDHB cohorts.
| RNSH – discovery cohort (n = 279) | SBH – validation cohort (n = 296) | RNSH and SBH – combined cohort (n = 575) | P-value | |
|---|---|---|---|---|
| Male, n (%) | 133 (48) | 149 (50) | 282 (49) | 0.48 |
| Probands, n (%) | 32 (11) | 25 (8) | 57 (10) | 0.23 |
| Genetic testing, n (%) | 260 (93) | 243 (82) | 503 (88) | <0.001b |
| Loss of function pathogenic variant, n (%) | 172 (62) | 179 (60) | 351 (61) | 0.77 |
| Birth order | ||||
| First, n (%) | 49 (18) | 120 (41) | 169 (29) | 0.43 |
| Second, n (%) | 47 (17) | 96 (32) | 143 (25) | |
| Third or later, n (%) | 39 (14) | 64 (22) | 103 (18) | |
| Not available, n (%) | 144 (52) | 16 (5) | 160 (28) | |
| Family size: children | ||||
| One, n (%) | 15 (5) | 20 (7) | 35 (6) | 0.08 |
| Two, n (%) | 71 (25) | 120 (41) | 190 (33) | |
| Three or more, n (%) | 188 (67) | 156 (53) | 345 (60) | |
| Not available, n (%) | 5 (2) | 0 | 5 (1) | |
| Family size: generations | ||||
| Two; n families (%) | 18 (44) | 11 (27) | 29 (35) | 0.02a |
| Three; n families (%) | 23 (56) | 25 (61) | 48 (59) | |
| Four; n families (%) | 0 | 5 (12) | 5 (6) |
aP-value < 0.05; bP-value < 0.01.
The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort (Table 3), 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort (Table 4 and Fig. 2). For the discovery cohort, TRD was apparent when analysing for each of paternal inheritance, loss of function PV, mutation within the proximal region of the gene (exons 1–3 and up to IVS3), male sex, and the second generation from the proband (Table 3). No parent-of-origin effect was observed in the combined cohort. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) if families with incomplete family size data were excluded and 0.58 (P < 0.001) if probands were excluded. Of the 72 individuals who did not have genetic testing, 36 were younger than 20 years of age; after excluding these participants, the transmission ratio was 0.59 (P < 0.001). No factors predicted TRD on a generalized linear model with binary logistic regression (Tables 5 and 6).
Forest plot of transmission ratio in SDHB families in the combined cohort.
Citation: Endocrine-Related Cancer 30, 5; 10.1530/ERC-22-0233
Transmission ratio in SDHB families in the discovery cohort.
| Actual (95% CI) | Expected | P-value | |
|---|---|---|---|
| Cohort that underwent genetic testing (n = 260) | 0.59 (0.53–0.65) | 0.50 | 0.005b |
| Probands excluded (n = 228) | 0.53 (0.46–0.60) | 0.50 | 0.40 |
| Cohort with complete family size data (n = 30) | 0.63 (0.44–0.80) | 0.50 | 0.20 |
| Cohort excluding those <20 years of age without genetic test (n = 269) | 0.57 (0.51–0.63) | 0.50 | 0.03a |
| Paternal inheritance (n = 123) | 0.62 (0.53–0.70) | 0.50 | 0.01a |
| Maternal inheritance (n = 124) | 0.57 (0.47–0.65) | 0.50 | 0.18 |
| Loss of function pathogenic variant (n = 157) | 0.59 (0.51–0.67) | 0.50 | 0.03a |
| Missense pathogenic variant (n = 103) | 0.58 (0.48–0.68) | 0.50 | 0.12 |
| Pathogenic variant in exons 1–3 or intronic region up to IVS3 (n = 193) | 0.59 (0.52–0.66) | 0.50 | 0.01a |
| Pathogenic variant in exons 4–8 or intronic region from IVS3 to IVS6 (n = 60) | 0.57 (0.43–0.69) | 0.50 | 0.37 |
| Male sex (n = 125) | 0.59 (0.51–0.68) | 0.50 | 0.04a |
| Female sex (n = 135) | 0.58 (0.49–0.67) | 0.50 | 0.06 |
| Second generation (n = 156) | 0.64 (0.56–0.72) | 0.50 | <0.001b |
| Third generation (n = 104) | 0.51 (0.41–0.61) | 0.50 | 0.92 |
| Birth order firstc (n = 13) | 0.69 (0.39–0.91) | 0.50 | 0.27 |
| Birth order secondc (n = 10) | 0.60 (0.26–0.89) | 0.50 | 0.75 |
| Birth order third or laterc (n = 6) | 0.50 (0.12–0.88) | 0.50 | 1.0 |
| Family size one childc (n = 1) | 1.0 (0.25–1.0) | 0.50 | 1.0 |
| Family size two childrenc (n = 12) | 0.58 (0.28–0.85) | 0.50 | 0.77 |
| Family size three or more childrenc (n = 17) | 0.65 (0.38–0.86) | 0.50 | 0.33 |
aP-value < 0.05; bP-value < 0.01; cAnalysis in families with complete family size data.
Transmission ratio in SDHB families in the combined cohort.
| Actual (95% CI) | Expected | P-value | |
|---|---|---|---|
| Cohort that underwent genetic testing (n = 503) | 0.63 (0.58–0.67) | 0.50 | <0.001b |
| Probands excluded (n = 446) | 0.58 (0.53–0.63) | 0.50 | <0.001b |
| Cohort with complete family size data (n = 273) | 0.67 (0.61–0.72) | 0.50 | <0.001b |
| Cohort excluding those < 20 years of age without genetic test (n = 539) | 0.59 (0.54–0.63) | 0.50 | <0.001b |
| Paternal inheritance (n = 234) | 0.64 (0.57–0.70) | 0.50 | <0.001b |
| Maternal inheritance (n = 252) | 0.64 (0.57–0.69) | 0.50 | <0.001b |
| Loss of function pathogenic variant (n = 297) | 0.66 (0.60–0.71) | 0.50 | <0.001b |
| Missense pathogenic variant (n = 206) | 0.59 (0.52–0.66) | 0.50 | 0.02a |
| Pathogenic variant in exons 1–3 or intronic region up to IVS3 (n = 344) | 0.63 (0.58–0.68) | 0.50 | <0.001b |
| Pathogenic variant in exons 4–8 or intronic region from IVS3 to IVS6 (n = 152) | 0.62 (0.54–0.70) | 0.50 | 0.005b |
| Male sex (n = 236) | 0.66 (0.59–0.72) | 0.50 | <0.001b |
| Female sex (n = 264) | 0.60 (0.54–0.66) | 0.50 | 0.001b |
| Second generation (n = 294) | 0.66 (0.60–0.71) | 0.50 | <0.001b |
| Third generation (n = 194) | 0.60 (0.53–0.67) | 0.50 | 0.005b |
| Birth order firstc (n = 110) | 0.75 (0.65–0.82) | 0.50 | <0.001b |
| Birth order secondc (n = 90) | 0.67 (0.60–0.76) | 0.50 | 0.002b |
| Birth order third or laterc (n = 56) | 0.55 (0.42–0.69) | 0.50 | 0.50 |
| Family size one childc (n = 15) | 1.00 (0.78–1.00) | 0.50 | <0.001b |
| Family size two childrenc (n = 112) | 0.72 (0.63–0.80) | 0.50 | <0.001b |
| Family size three or more childrenc (n = 146) | 0.59 (0.51–0.67) | 0.50 | 0.004b |
aP-value < 0.05; bP-value < 0.01; cAnalysis in families with complete family size data.
Generalized linear model with binary logistic regression of predictors of TRD in the combined cohort of participants that underwent genetic testing (n = 503).
| Predictors of TRD | P-value | OR (95% CI) |
|---|---|---|
| Male | 0.41 | 0.85 (0.69–1.24) |
| Loss of function pathogenic variant | 0.21 | 1.29 (0.87–1.91) |
| PV in exons 1–3 or intronic region up to IVS3 | 0.79 | 0.94 (0.62–1.44) |
| Paternal inheritance | 0.96 | 0.99 (0.68–1.44) |
| Test | P-value | χ2 |
| Overall model likelihood ratio test (omnibus test) | 0.99 | 2.39 |
Generalized linear model with binary logistic regression of potential predictors of TRD in the combined cohort of families with complete family size data (n = 273).
| Predictors of TRD | P-value | OR (95% CI) |
|---|---|---|
| Male | 0.23 | 0.71 (0.41–1.24) |
| Loss of function pathogenic variant | 0.06 | 1.73 (0.97–3.11) |
| PV in exons 1–3 or intronic region up to IVS3 | 0.83 | 0.93 (0.49–1.78) |
| Paternal inheritance | 0.99 | 1.00 (0.56–1.80) |
| Birth order | 0.67 | 1.06 (0.80–1.41) |
| Family size (number of children) | 0.37 | 1.10 (0.88–1.41) |
| Test | P-value | χ2 |
| Overall model likelihood ratio test (omnibus test) | 0.12 | 10.05 |
Transmission ratio analysis was replicated for the SDHD cohort at St Bartholomew’s Hospital: 81 patients from 13 families, most commonly of 3 generations (range 2–4) and with 2 children per nuclear family (range 1–5) (Table 7). Phenotype expression was dependent on paternal inheritance, as expected. Of the 61 participants with confirmed germline testing, 43 harboured an SDHD PV (Supplementary Table 2), which represents a significant distortion in transmission ratio: 0.70 (P = 0.0019). TRD in SDHD was upheld even when assuming that a Mendelian 50% of those with unknown genotypes were carriers (0.65, P = 0.0073). Neither clinical centre had SDHA or SDHC cohorts of sufficient size for analysis.
Baseline characteristics of the SDHD cohort.
| SDHD cohort, n | 81 |
|---|---|
| Male, n (%) | 45 (57) |
| Probands, n (% | 13 (16) |
| Genetic testing, n (%) | 61 (75) |
| Loss of function pathogenic variant, n (%) | 18 (22) |
| Birth order | |
| First, n (%) | 39 (48) |
| Second, n (%) | 25 (31) |
| Third or later, n (%) | 17 (21) |
| Family size: children | |
| One, n (%) | 10 (12) |
| Two, n (%) | 14 (17) |
| Three or more, n (%) | 9 (11) |
| Family size: generations analysed | |
| Two, n (%) | 41 (51) from 8 families |
| Three, n (%) | 25 (31) from 3 families |
| Four, n (%) | 15 (18) from 2 families |
Discussion
A TRD of 60% in favour of the SDHB PV being transmitted was evident in our cohort. In the discovery cohort, it appeared that TRD was associated with particular variables, but the analysis was limited by incomplete family data and insufficient power. In the combined cohort, TRD was observed irrespective of sex, parent of origin, loss of function PV, or location of the mutation within the proximal or distal region of the gene. Given that rates of genetic testing differed between centres, we assessed complete family data. When families with incomplete family size data were excluded, TRD was still noted. When probands were excluded, TRD still occurred, suggesting TRD was not due to oversampling of cases (Gemechu et al. 2020). We considered the possibility of bias in young individuals not undergoing genetic testing due to being asymptomatic since the median age of disease diagnosis is 37 years (Davidoff et al. 2022), but after the exclusion of participants younger than age 20 years without a genetic test, TRD was still observed. Birth order third or later was not associated with TRD, likely due to insufficient power (n = 56), given that heterogeneity was absent on Levene’s test. As TRD was consistently observed across different variables, the finding that no particular factors predicted TRD on the generalized linear model was unsurprising.
The 60% distortion in transmission of pathogenic SDHB alleles is consistent with the magnitude of other examples of TRD: PVs of the tumour suppressor gene for retinoblastoma, RB-1, were found to have 63% transmission from affected males to sons (Naumova & Sapienza 1994); STX16-GNAS mutations in autosomal dominant pseudohypoparathyroidism type Ib were transmitted to 63% of offspring (Kiuchi et al. 2021); mutated alleles in long-QT syndrome conferred 55% transmission to female offspring (Imboden et al. 2006); and a study of embryos from preimplantation genetic testing for myotonic dystrophy type 1 found that 59% harboured the CTG nucleotide repeat expansion (Dean et al. 2006).
It has been suggested that the phenomenon of anticipation is apparent in SDH-deficient disease (Antonio et al. 2020), albeit without a trinucleotide repeat expansion to facilitate this in a classical way. Whilst an earlier age of tumour diagnosis was documented in some subsequent generations, this was attributed to an early age of screening and surveillance; furthermore, this phenomenon was not borne out across our 82 families to suggest a genuine pattern of an underlying biological change in disease penetrance across the generations.
Limitations to this study included some uncollected data that could hypothetically influence the interpretation of inheritance patterns, such as age of parenthood, miscarriage rate, and birth order. The sample size was robust relative to accessible cohorts of rare disease but may limit extrapolation from statistical significance to biological significance, such as with the question of a parent-of-origin effect on transmission. However, to counter potential sources of bias, we tested the sensitivity of our results by excluding, in turn, possible confounders: families with incomplete family size data, probands, and untested participants less than 20 years old. None of these analyses significantly altered the main finding of TRD in favour of SDHB PVs.
The reason for a TRD in SDH-B and -D is unknown. We hypothesize the mechanism could occur at the post-fertilization stage and arise as a selective advantage, perhaps for adapting to hypoxia; however, assessing the timing and mechanisms for TRD was beyond the scope of the present study. It is fascinating to consider how an embryonic survival advantage for hypoxia/pseudo-hypoxia might then be accompanied by variably penetrant tumour risk in postnatal life. Intriguingly, several tumour suppressor genes and oncogenes have also been demonstrated to manifest TRD in favour of the mutant allele (Huang et al. 2013), including CDKN1C (Sazhenova & Lebedev 2008), HRAS1, and SIRT3 (De Rango et al. 2008). Moreover, CDKN1C has been implicated in the pathogenicity of SDHAF2 and SDHD mutations when arising from loss of maternal chromosome 11 (Hoekstra et al. 2017), whereas HRAS and sirtuin-3 both regulate mitochondrial function (Dard et al. 2022, Papa & Germain 2014).
The clinical relevance of distortion in the transmission of SDH-B and -D mutations is immediately apparent: a TRD that favours the potential for tumourigenesis has significant implications for genetic counselling of all carriers. The role of pre-implantation genetic diagnosis is arguably stronger when the odds are against the likelihood of healthy offspring. We encourage other centres to analyse their cohorts similarly to validate our findings, with a view to updating guidelines on genetic counselling. An understanding of the mechanism behind TRD in SDH, where the heterozygous state may have an advantage, might lead to insights that later allow interventions in carriers to decrease the risk of tumour development.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-22-0233.
Declaration of interest
The authors declare no overt competing interests but are in receipt of funding as follows: DFD is supported by the RACP Foundation (2022RES00038). ESL has been supported by Barts Charity (MGU0468) and the Medical Research Council UKRI (MR/W001101/1) during this study. SAA receives funding from Barts Charity (MGU0437). DEB and RCB receive funding from Perpetual (Hillcrest Foundation).
Funding
This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
S A Akker and R J Clifton-Bligh authors are Senior co-authors. Conceptualization: RCB; Data curation: DFD, ESL, DEB, YS, ED, JRB; Formal analysis: DFD, ESL, ED; Writing – original draft: DFD, ESL; Writing – review & editing: RCB, SAA
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